Project Summary Little is known about the cellular mechanisms involved in generating HIV bnAbs. BnAbs are very difficult to develop and have traits indicative of extensive affinity maturation in germinal centers (GC). One hypothesis is that Tfh cells in the GC are important for driving the development of HIV bnAbs. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help and are necessary and limiting for GCs. (1) How do Tfh cells enhance HIV bnAb development? Is it related to Tfh quantities and/or selective functions? (2) How is somatic hypermutation related to the likelihood of bnAb development? GC SHM activity is necessary for bnAb development, but is there a quantitative relationship? (3) What B cell characteristics are critical to bnAb development? We hypothesize that bnAb development in HIV+ patients may be primarily dependent on (A) unusual B cell repertoire features, such as glycan reactivity; (B) a particular category of B cell response; and/or (C) overall sequence space explored by SHM.